COVID‐associated arthritis after severe and non‐severe COVID‐19: A systematic review

Abstract Aim Since the coronavirus outbreak became a global health emergency in 2020, various immune‐based effects, such as inflammatory arthritis (IA), have been recorded. This study aimed to determine the role of COVID‐19 severity on post‐COVID arthritis. Methods We systematically reviewed 95 patients who developed arthritis after severe and non‐severe COVID‐19 infection by searching the databases, including PubMed, SCOPUS, and EMBASE. We used the term “COVID‐associated arthritis” because there was no definite diagnostic method for classifying arthritides after COVID‐19 infection, and the diagnosed arthritis types were based on the authors' viewpoints. Results After evaluating the data between the two severe and non‐severe COVID‐19‐infected groups of patients, the results showed that the COVID‐19 severity may affect the pattern of joint involvement in IA. In both groups, combination therapy, including oral nonsteroidal anti‐inflammatory drugs with different types of corticosteroids, was the most common treatment. In addition, the mean age and comorbidities rate was higher in the severe COVID‐19 group. Even though the patients in the severe COVID‐19 group developed more serious COVID‐19 symptoms, they experienced milder arthritis with better outcomes and more delayed onsets that required less aggressive therapy. Conclusion We conclude that there may be an inverse relationship between COVID‐19 severity and arthritis severity, possibly due to weaker immunity conditions following immunosuppressant treatments in patients with severe COVID‐19.

][4] IA is non-septic arthritis that includes conditions in which the body's defensive mechanisms attack joint tissues rather than germs or viruses.Common types of IA comprise reactive arthritis (Re-A), rheumatoid arthritis (RA), ankylosing spondylitis (AS), psoriatic arthritis (PA), and gout arthritis (GA). 5Nearly 1% of all cases of acute IA are considered to have a viral etiology. 6Re-A is the most common type of COVID-associated IA that occurs as a "reaction" to an infection elsewhere in the body.Re-A often appears in patients without a history of rheumatic and musculoskeletal diseases (RMDs).It may only be presented with peri-articular manifestations such as tenosynovitis, tendinitis, enthesitis, dactylitis, and bursitis or in conjunction with arthritis. 7,8iral infections such as the SARS-CoV-2 virus can solely trigger musculoskeletal manifestations with a nonimmune pathway by directly invading joint tissues and cells; this event is called viral arthritis.Diagnosing and confirming viral arthritis can be challenging because, up to this date, there are no accepted diagnostic criteria to distinguish viral arthritis from post-viral Re-A. 8Our study used the term "COVID-associated arthritis" interchangeably to include both viral arthritis and postviral IA.
Here we have systematically reviewed COVIDassociated arthritis in patients after severe and nonsevere COVID-19 infection by aggregating both post-COVID inflammatory and viral arthritides studies.
severe COVID-19.The JBI checklist was used to assess the quality of selected studies in parallel by two reviewers (M.Z. and P. A.), then the results were structured in a qualitative synthesis.

| Study characteristics
Our search primarily included all published articles in any language until Febuary 20, 2023, and 271 papers were collected.Duplicate reports were initially removed; then, the titles, abstracts, and full texts were separately reviewed by two authors (M.Z. and P. A.). Non-English, review, and irrelevant articles were excluded.Cases with post-COVID arthritis, including case reports, case series, letters, editorial papers, comments, and conferences, were included for eligibility assessment, and documents with inadequate clinical data were excluded.Finally, 41 case reports (45 patients, Table 1)  and 5 case series (50 patients, Table 2), [51][52][53][54][55] with a total number of 95 patients (46 studies), were included in this systematic review. The fow diagram for the search of databases is given in Figure 1.
According to the nationalities of reported cases, we made a map chart for the distribution of COVIDassociated arthritis cases worldwide, shown in Figure 2.
While six patients were diagnosed with RMD flareups, 54,55 9 cases had a history of RMD; in one article, the patient with a Re-A diagnosis had a history of goutarthritis; however, the author reported this case as a Re-A. 31Also, two patients with a history of nail psoriasis 25 and undifferentiated IA 35 were reported as IA and Re-A, respectively.Other patients experienced their first episode of arthritis by being diagnosed as post-COVID Re-A or viral arthritis (58 cases), post-COVID AS or sacroiliitis (10 cases), COVID-related arthritis (5 cases), and other IAs (2 cases); these classifications of arthritis types were based on authors' report.
Although 57 patients gained complete or significant remission after treatment and follow-up, 7 patients acquired partial remission, 1 experienced a relapse of symptoms, 54 and 2 had persistent arthritis with no improvement. 31,37Remission status was not mentioned in 10 cases. 49,52The history of recent vaccinations against the SARS-CoV-2 virus was mentioned in 2 patients. 35,54
While three patients were diagnosed with RMD flareups and had an RMD history, 19,55  Abbreviations: ANA, antinuclear antibodies; anti-CCP, anti-cyclic citrullinated peptide antibodies; AS, ankylosing spondylitis; BPH, benign prostatic hyperplasia; CPP, calcium pyrophosphate; DLP, dyslipidemia; DM-2, diabetes mellitus-type2; F, female; HCQ, hydroxychloroquine; HLA-B27, human leukocyte antigen-B27; HTN, hypertension; IA, intra-articular; IDA, iron deficiency anemia; IM, intramuscular; IV, intravascular; M, male; MCP, metacarpophalangeal joint; MGUS, monoclonal gammopathy of undetermined significance; mono, monoarthritis; MSU, monosodium urate; MTP, metatarsophalangeal joint; MTX, methotrexate; ND, not done; NM, not mentioned; NSAID, nonsteroidal anti-inflammatory drug; NSCLC, non-small cell lung carcinoma; oligo, oligoarthritis; PA, psoriatic arthritis; poly, polyarthritis; pSS, primary Sjögren's syndrome; Re-A, reactive arthritis; RF, rheumatoid factor; RMD, rheumatic and musculoskeletal diseases; SCLE, subacute cutaneous lupus erythematosus; SF, synovial fluid; SSZ, sulfasalazine.arthritis (2 cases), and post-COVID undifferentiated arthritis (1 case).The prevalent form of joint involvement was the peripheral form reported in 18 patients, and three experienced axial involvement simultaneously.The peripheral form types comprised monoarthritis (in 4 patients), oligoarthritis (in 9 patients), and polyarthritis (in 4 patients).The most frequently involved joints were as follows: the knee, reported in 10 patients (bilateral in 5), and the ankle, in 7 patients (bilateral in 3); All affected joints are listed in Table 3.The location of peripheral arthritis was not mentioned in 1 patient. 19Peri-articular involvements of peripheral forms, such as enthesitis, tenosynovitis, and tendinitis, were seen in 3 cases. 41,53Dactylitis is another peri-articular manifestation noted in 1 patient without arthritis. 43nly one patient experienced extra-articular manifestations, including bilateral conjunctivitis, psoriatic skin lesions, oral lesions, and vulvitis, 43 and no positive STD test was documented.In addition, 1 patient out of 6 was HLA-B27 positive 43 ; 3 patients out of 17 were positive for other rheumatologic auto-antibodies, including RF in 2 patients, 19,30 HLA-B57 in 1 patient, 43 and anticitrullinated protein autoantibody in 1 patient. 19Synovial fluid culture and analysis of crystals were performed in 7 and 8 cases, respectively, and just two samples were positive for MSU crystals. 55e interval between COVID-19 symptoms and the onset of arthritis differs from zero days (simultaneous with COVID-19) to 3 months.22][23]30,41,43,51,53,55 Corticosteroids (in 10 cases) and NSAIDs (in 9 cases) were the most prevalent prescribed drugs for arthritis treatment.Monotherapy with steroids and NSAIDs was used in 4 and 5 patients, respectively.Corticosteroids were administered in different types comprising oral route in 6 patients, 21,22,30,43,51,55 intra-articular route in 1 patient, 41 and intramuscular route in 1 patient. 20rescribed forms of steroids were not noted in 2 cases. 54CQ as a kind of DMARDs was administered in 1 case. 51ll prescribed drugs are listed in Table 3, and 1 patient's arthritis subsided without treatment. 17Although 15 patients gained complete or significant remission after treatment or follow-up, 2 patients acquired partial symptom improvement 41,54 ; remission status was not mentioned in 1 case. 51atients' characteristics in both severe and non-severe groups are summarized in Table 3 and Figure 3.The association between age, sex, type of arthritis, the pattern of joint involvement, location of involved joints, extraarticular manifestation, lab tests, the onset of arthritis, treatment, outcome, and designated severe and nonsevere groups were assessed using χ 2 tests (Table 3).No association was determined (p > .05).Re-A, RA, AS, PA, and GA are common subgroups of IA that frequently arose after COVID-19 infection.Re-A and AS were repeatedly reported after infection with viruses such as SARS-CoV-2 and were presented as the first episode of arthritis in patients without RMD history.Re-A often occurs with asymmetric oligoarthritis of the lower limbs, especially the knee joint; AS is mainly copresent with axial involvement, called sacroiliitis; both AS and sacroiliitis are considered subgroups of spondyloarthropathies, that are associated with the HLA-B27 genetic marker. 56RA, PA, and GA are other chronic IA that can be flared up or first appear after viruses like SARS-CoV-2. 57Although these cases were reported during the coronavirus disease pandemic, other etiologies cannot be entirely excluded.
In this systematic review, we compiled all published data on patients with COVID-related arthritis.We summarized 95 included patients in two categories: COVID-associated arthritis following non-severe COVID-19 and COVID-associated arthritis following severe COVID-19 (Table 3).We used "COVIDassociated arthritis" because there were no definite diagnostic classifications for arthritides after COVID-19, and the arthritides types were based on the author's point of view.Previously, Farisogullari et al. used the "COVIDassociated arthritis" term instead of both Re-A and viral arthritis 8 ; However, we used this term to contain all common types of IA and viral arthritis.
Following our computation, 81.05% of the patients experienced asymptomatic, mild, or moderate COVID-19, and 18.95% underwent severe or critical COVID-19 infection, similar to the COVID-19 severity rate (19%). 58owever, the mortality rates are 54.64% for severe COVID-19 and 5% for non-severe COVID-19 infection, 59 which can mean most severe COVID-19 cases expired F I G U R E 3 Comparison of the pattern of joint involvements (A), location of involved joints (B), treatments (C), and outcomes (D) between two groups, based on percentage.AI, axial involvement; COSR, complete or significant remission; DA, dactylitis; DMARDs, disease-modifying anti-rheumatic drugs; MA, monoarthritis; NSAIDs, nonsteroidal anti-inflammatory drugs; OA, oligoarthritis; PA, polyarthritis; PR, partial remission; RONR, relapse or no remission; TTE, tenosynovitis, tendinitis, and enthesitis.before developing arthritis, and the actual rate of arthritis after severe COVID-19 could be doubled; consequently, we predict that COVID-severity may be a risk factor for the occurrence of post-COVID-arthritis.
All patients in the severe COVID-19 group were adults with a mean age of 53.05 ± 15.27 years, and 55.56% of them had at least one non-RMD comorbidity; on the other hand, in the non-severe COVID-19 group, 7.79% of cases were juveniles, and the mean age was 41.43 ± 16.45 years; and 32.46% mentioned at least one non-RMD comorbidity; which shows the fact that age and comorbidity are the most potent risk factors for severe COVID-19 outcomes. 60ccording to the authors' reports, 92.21% of patients in the non-severe COVID-19 group were diagnosed with non-RMD arthritis and 7.79% with RMD flare-ups; however, 11.69% of them declared a history of RMDs and 7.79% had positive rheumatic autoantibodies.We included all COVID-related arthritides, not solely Re-A, to avoid missing any related data or cases.In the severe COVID-19 group, 16.67% of patients were diagnosed with RMD flare-ups and reported a history of RMDs with positive rheumatic autoantibodies; the rest experienced their first episode of IA.Despite the fact that there were no significant differences in HLA-B27 positivity between the two groups and most of the positive HLA-B27 patients were cases with sacroiliitis or cases of nonaxial Re-As. 56urthermore, two patients who experienced arthritis after non-severe COVID-19 declared a history of recent vaccine injections.One of them reported a SARS-CoV-2 vaccine (Biontech/Pfizer) injection 9 days before arthritis, whereas the onset of COVID-infection occurred 8 weeks before arthritis, 54 so we think it was post-COVIDvaccine arthritis rather than post-COVID-arthritis, and this situation was numerously reported, before. 3In the second case, a SARS-CoV-2 vaccine (inactivated Sinovac) was injected 2 months before arthritis and COVID-19 symptoms 35 ; in this case, both COVID-19 and COVIDvaccine can be the triggers of arthritis.
While in the non-severe COVID-19 group, common peripheral joint involvement patterns consist of oligoarthritis (27.27%), monoarthritis (25.97%), and polyarthritis (25.97%), in the severe COVID-19 group, the proportion of each pattern was different, oligoarthritis (50%) was the most prevalent, monoarthritis (22.22%), and polyarthritis (22.22%) were following ones (Figure 3); we assume that current distribution of patterns in the non-severe group was because of the unmentioned cases (11.53%) that could change the oligoarthritis pattern percentage in this group.The knee was the most affected joint in both groups, perhaps due to the high number of Re-A among the cases 56 (Figure 3).
As the treatments of arthritis were based on age, comorbidities, RMDs history, arthritis severity, and other personal conditions, we cannot precisely define the best treatment; nevertheless, in both groups, polytherapy (or combination therapy) was more common than monotherapy, and it often included oral NSAIDs with different types of corticosteroids (Figure 3).More aggressive treatments such as DMARDs, TNF-α inhibitors, immunomodulators, and JAK inhibitors were administered more frequently in the non-severe COVID-19 group.However, the complete or significant remission rate was higher in the severe COVID-19 group (74.03% in the nonsevere and 83.33% in the severe group), and relapse or no remission rate was lower in the severe group (3.90% in the non-severe and 0% in severe) (Figure 3).The late onset (>1 week) of arthritis after COVID-19 symptoms in nonsevere and severe COVID-19 were 59.74% and 88.89%, respectively.Overall, even though the patients in the severe COVID-19 group developed more serious COVID-19 symptoms, they experienced milder arthritis with better outcomes and more delayed onsets that required less aggressive therapy; therefore, we suppose that weaker immunity situation in the severe COVID-19 group, due to aggressive corticosteroids therapy or other aggressive immunosuppressant treatments during hospitalization for COVID-19 infection, causes increased immunemediated complications following COVID-19.The pathogenesis of post-viral IA is partially understood.However, one of the hypothetical mechanisms mediating the activation of the inflammatory process is molecular mimicry, which is supposed to be responsible for evoking autoimmune responses in susceptible individuals. 4,18any reviews have been conducted to collect COVID-related arthritis before, 3,7,8,23,26,32 but there are some differences between this comprehensive review and them.As mentioned, we collected all IA types following COVID-19, but others only gathered Re-A or viral arthritis.We reviewed the case series and the case reports altogether, with a total number of 95 cases.In contrast, others did not review any case series and included fewer patients (at most 33 cases 8 ).In addition, we listed data in two different non-severe and severe COVID-19 categories to compare them and detect the probable relations between COVID-infection severity and post-COVID arthritis severity, which was novel.
Besides all the new data and evaluations, our study had some limitations too; for example, no observational study was done, there were a lot of unmentioned data in some papers, and some cases were better documented than others, leading to variations in the quality of papers.To decrease the risk of bias and improve the quality of evaluations, we listed the case reports and the case series in two separate tables (Tables 1 and 2).
This study compares COVID-associated arthritis in two non-severe COVID-19 and severe COVID-19 categories by collecting data from 95 cases.We conclude that the prevalence of COVID-associated arthritis may increase with COVID-19 severity.However, there is an inverse relationship between COVID-19 severity and arthritis severity, probably because of weaker immunity conditions following immunosuppressant therapy in patients with severe COVID-19.We suggest that all non-severe COVID-19 patients, even asymptomatic ones, need nonaggressive immunosuppressant treatments (during COVID-19 infection) to alleviate the immune-based complications, specifically IA.

3
Summary of patients' characteristics and their repetition (and percentage) among reported case.

T
A B L E 3 (Continued)The onset of arthritis after non-severe COVID-19